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Dead or Alive? Nanopatrols Report

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Science Translational Medicine  06 Mar 2013:
Vol. 5, Issue 175, pp. 175ec38
DOI: 10.1126/scitranslmed.3006039

In the quantum mechanics realm, it’s useful to think about Schrödinger’s cat as being dead or alive. But when it comes to cellular therapies, knowledge of the survival state of cells is crucial to clinical success. Now, Chan et al. describe a noninvasive imaging technique that permits probing of cell viability in vivo.

The use of hydrogel-encapsulated cells has emerged as a potential treatment for diverse diseases. However, clinical implementation is limited by poor cell survival in vivo after delivery. The limited knowledge about factors that affect cell survival and how to prolong cell viability hampers the optimization and application of these therapies. Existing methods that use reporter gene–based imaging, such as luciferase bioluminescence, are robust in tracking cell viability but limited to small animals because the light absorption and scattering by tissues attenuates the light, thus limiting detection. To decipher the factors that determine cell viability in vivo, the authors developed a noninvasive imaging technique based on magnetic resonance imaging (MRI) that enables real-time assessment of cell viability. Although validated in mouse models to enable comparison with conventional bioluminescent techniques, this method can be translated to the clinic because MRI permits high-resolution imaging in humans.

As a proof of concept, Chan et al. attempted to treat liver failure in mice by introducing, subcutaneously, hepatocytes housed in a semipermeable alginate microcapsule. The capsule protects hepatocytes from the host immune system while allowing exchange of nutrients. The microcapsules were placed adjacent to L-arginine–based nanosensors. Because cell death is associated with acidification of extracellular pH, L-Arg serves as a pH-sensitive reporter that changes MRI contrast as a result of rapid proton exchange with surrounding water. MRI signals changed dramatically after induction of cell apoptosis in the implanted capsules, as corroborated by means of immunofluorescence and conventional bioluminescence imaging. The authors also used MRI to show that immune cell invasion can be inhibited by the coadministration of immunosuppressant drugs, as is implemented in the clinic. Indeed, immunosuppressants prolonged cell survival in mouse models as compared with untreated immunocompetent mice.

The L-Arg nanosensors can be paired with other cell types and potentially modified to target specific cell populations even outside the polymeric capsules and may prove invaluable as a tool for drug screening. Data gained from use of this tool should improve our understanding of what is killing the cells and how to prevent it. The components of the nanosensor and its delivery vehicle are known to be safe for use in humans; however, cytocompatibility and clinical effectiveness must be tested.

K. W. Y. Chan et al., MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted- cell viability. Nat. Mater 12, 268–275 (2013). [Abstract]

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